Role of macrophages in inflammatory lymphangiogenesis: Enhanced production of vascular endothelial growth factor C and D through NF-kappaB activation.
The close association of inflammation, angiogenesis and cancer progression is now highlighted, and in this study we especially focused on a close association of inflammation and lymphangiogenesis. We found that proinflammatory cytokine, interleukin-1beta (IL-1beta), could induce lymphangiogenesis in mouse cornea through enhanced production of potent lymphangiogenic factors, VEGF-A, VEGF-C and VEGF-D. IL-1beta-induced lymphangiogenesis, but not angiogenesis, was inhibited by administration of a selective anti-VEGF receptor-3 (VEGFR-3) neutralizing antibody. And in mouse cornea we observed recruitment of monocyte/macrophages and neutrophils by IL-1beta implanted cornea. Depletion of macrophages by a bisphosphonate encapsulated in liposomes inhibited this IL-1beta-induced lymphangiogenesis and also up-regulation of VEGF-A, VEGF-C, and VEGF-D. Furthermore, IL-1beta-induced lymphangiogenesis and angiogenesis were suppressed by NF-kappaB inhibition with marked suppression of VEGF-A, VEGF-C, and VEGF-D expression.
Watari
Kosuke
K
Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
Nakao
Shintaro
S
Fotovati
Abbas
A
Basaki
Yuji
Y
Hosoi
Fumihito
F
Bereczky
Biborka
B
Higuchi
Ryuichi
R
Miyamoto
Tomofumi
T
Kuwano
Michihiko
M
Ono
Mayumi
M
D000818:Animals; D049109:Cell Proliferation; D003315:Cornea / Q000098:blood supply / Q000187:drug effects / Q000276:immunology; D004164:Diphosphonates / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology* / Q000494:pharmacology; D007634:Keratitis / Q000276:immunology*; D042583:Lymphangiogenesis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000276:immunology; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D042643:Vascular Endothelial Growth Factor D / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology
D004164:Diphosphonates; D053583:Interleukin-1beta; D016328:NF-kappa B; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D016222:Fibroblast Growth Factor 2